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© 2003 American Society for Clinical Oncology New Malignancies After Blood or Marrow Stem-Cell Transplantation in Children and Adults: Incidence and Risk Factors
From the Departments of Pediatrics and Medicine, Blood and Marrow Transplant Program, University of Minnesota, Minneapolis, MN. Address reprint requests to K. Scott Baker, MD, Pediatric Blood and Marrow Transplant Program, Department of Pediatrics, University of Minnesota, 420 Delaware Street SE, Mayo Mail Code 484, Room D-557, Minneapolis, MN 55455; email: baker084{at}tc.umn.edu.
Purpose: To determine the incidence and risk factors for the development of new malignancies occurring after stem-cell transplantation (SCT). Patients: Between January 1, 1974, and March 31, 2001, 3,372 patients underwent SCT at the University of Minnesota. From these transplants, 147 posttransplant malignancies (PTMs) were identified in 137 patients. Results: Excluding nonmelanoma skin cancers (n = 19) and carcinoma-in-situ (n = 5), the remaining 123 cases represented an 8.1-fold (95% confidence interval [CI], 6.7 to 9.6) increased risk of a PTM, an excess risk of 102.7 cases/10,000 persons/yr (age and sex adjusted). This includes a significantly elevated risk for developing myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML; standardized incidence ratio [SIR] = 300; 95% CI, 210 to 406), non-Hodgkin’s lymphoma including posttransplant lymphoproliferative disorder (PTLD; SIR = 54.3; 95% CI, 39.5 to 41.1), Hodgkin’s disease (SIR = 14.8; 95% CI, 3.9 to 32.9), or solid tumors overall (SIR = 2.8; CI, 2.0 to 3.7) and in specific for melanoma, brain, and oral cavity tumors. The cumulative incidence for the development of any PTM was 6.9% (95% CI, 5.2 to 8.6) at 20 years post-SCT. For PTLD (n = 43), the cumulative incidence plateaued at 1.4% (95% CI, 1.0 to 1.8) by 10 years post-SCT. For MDS or AML, the cumulative incidence plateaued at 1.4% (95% CI, 0.9 to 1.9) by 10 years post-SCT. The cumulative incidence of developing a solid tumor did not plateau and was 3.8% (95% CI, 2.2 to 5.4) at 20 years post-SCT. Conclusion: These data reveal that the risk of PTMs, especially solid tumors, continues to increase even 20 years after transplant, necessitating long-term close follow-up for these patients.
THE NUMBER and length of follow-up for survivors after successful hematopoietic stem-cell transplant (SCT) is increasing. With this increase, recognition of the types of long-term complications that can occur after SCT, including the development of posttransplant malignancies (PTMs), is becoming more important. Although studies exist that describe the risk factors and incidence of PTMs, the population of transplant survivors with 20 or more years of follow-up from those studies is small, and few studies report on the unique concerns regarding the population of patients that have been transplanted as children. New malignancies occurring after SCT fall into three general categories: solid tumors, hematologic malignancies (primarily therapy-related myelodysplastic syndrome and acute myeloid leukemia [t-MDS/AML]), and posttransplant lymphoproliferative disorder (PTLD). For solid tumors, the incidence in the largest series to date—more than 19,000 patients—was found to be 2.2% at 10 years and 6.7% at 15 years.1 In a similar report of the European experience, after 1,036 consecutive transplants the actuarial incidence of a solid tumor post-SCT was 3.5% at 10 years and 12.8% at 15 years.2 Also available are single-institution data from the University of Minnesota (Minneapolis, MN)3 and the City of Hope (Duarte, CA),4 where the actuarial incidence of developing a solid tumor post-SCT has been reported to be 5.6% at 13 years and 6.1% at 10 years, respectively. The third category of PTM, t-MDS/AML, has been a recognized complication of chemotherapy and/or radiation therapy delivered as treatment for a variety of malignancies5–7 and after high-dose chemoradiotherapy and autologous stem-cell rescue.3,8–11 Actuarial risk estimates for t-MDS/AML after autologous SCT in patients with lymphomas ranged from 3% to 19.8% from analyses with at least 5 years of follow-up.9 A slightly lower incidence was reported for patients undergoing autologous SCT for breast cancer12 (1.6% at 4 years) or advanced-stage germ-cell tumors13 (1.3% at 52 months). The last major category of PTMs is lymphoproliferative disorders that develop after stem-cell and solid-organ transplants and that occur in association with two primary factors: intense immunosuppression and, in most but not all cases, the proliferation of Epstein-Barr virus after transplant.14–17 Fortunately, in the overall SCT population from most large studies, the incidence of PTLD has been reported to be low, between 1.0% and 1.6%;3,18,19 however, the occurrence of PTLD after SCT is frequently fatal.17 A limitation of most of the available data on PTM is that little has been published about children and how their risks compare to those of adults. Only two studies address this issue directly. In the first study,1 for children less than 10 years of age, the risk of any PTM was 36.6 times higher than expected, and in the second study, limited to children with acute leukemia undergoing SCT, this risk was 45 times higher.19 In both studies, the risk of PTM was inversely correlated with age. The purpose of this study was to update and significantly expand our cohort of SCT patients at the University of Minnesota and to describe the occurrence of PTM with regard to age-specific risks, long-term incidence, and outcome in these patients.
Patients Between January 1, 1974, and March 31, 2001, 3,372 consecutive SCTs were performed at the University of Minnesota for a variety of malignant and nonmalignant disorders. All transplants were performed under protocols approved by the Human Subjects Committee of the University of Minnesota, and all subjects or their guardians provided signed informed consent. All peritransplant and posttransplant data were prospectively collected and maintained in a computerized database in the Biostatistical Support Group of the SCT program. Ongoing patient follow-up was performed in the outpatient clinics at the University of Minnesota, or, for patients that were no longer returning for follow-up, requests for follow-up information by contact with the patient or their referring physician were attempted at least once every 18 months. Data on major long-term follow-up events (including development of a PTM) were collected and maintained in the SCT program database. For this analysis, database records were searched and identified 147 invasive cancers (distinct from the previous cancer diagnosis) that had developed post-SCT in 137 patients. For each PTM, clinical data including date of diagnosis, type of malignancy (including copies of pathology reports), site of occurrence, and outcome were obtained. Each new malignancy record and pathology report was reviewed (K.S.B) to verify the accuracy of database entries. Fifty-three of these PTMs have been reported previously,3,17 and those records were reviewed again and updated for the current analysis.
Patient characteristics are detailed in Table 1
Statistical Methods For the entire cohort, the number of person-years at risk was calculated from the date of SCT until the date of diagnosis of PTM, date of death or last contact, or March 31, 2001, whichever came first. Data from the Surveillance, Epidemiology, and End-Results registry (SEER, 1973 to 1998)20 were used to determine age- and sex-specific incidence rates for all invasive solid tumors, AML, chronic myeloid leukemia (CML), non-Hodgkin’s lymphoma, and HD and for all cancers combined. Standardized incidence ratios (SIRs) were then calculated by obtaining the ratio of the observed to the expected number of cases, and 95% confidence intervals (95% CIs) were calculated.21 The absolute (excess) risk was calculated as the observed minus the expected number of cases of PTM per 10,000 patients per year. The cumulative incidence of developing a PTM over time was calculated by treating deaths from other causes as competing risks.22 Among patients that developed a PTM, we estimated the survival rate by the Kaplan-Meier method.23 Cox regression techniques24 were used to evaluate the independent effect of study variables on the development of specific malignancies. Variables included in the multiple regression analysis were donor type, primary diagnosis, age, sex, conditioning regimen, T-cell depletion, time-dependent onset of acute graft-versus-host disease (GVHD), HLA disparity, race, year of transplant, and stem cell source. All factors were tested for the proportional hazards assumption.24
Since the first analysis of the PTM experience at the University of Minnesota was published, 6 additional years of patient follow-up and accrual have taken place. Median follow-up is 5 years (range, 0.5 to 25 years). The total number of accumulated person-years of follow-up is now 10,494 person-years. The specific PTMs that have developed are listed in Table 3  .
Risk and Incidence of PTM For calculations of SIR and excess risk, nonmelanoma skin cancers (basal cell and squamous cell, n = 19) and carcinoma-in-situ (n = 5) were excluded because these are not captured in the SEER cancer reporting mechanism. For this cohort, the overall risk of developing a PTM was 8.1 times higher (95% CI, 6.72 to 9.57) than would be expected in the general population, which accounts for an excess risk of 102 cancers per 10,000 persons/yr (Table 4 ). If PTLD was excluded from this calculation, the SIR decreased to 5.4 and the excess risk decreased to 63. For individual hematopoietic cancers, the SIR for the development of MDS or AML was the highest at 300 (95% CI, 210 to 406), and the risk of PTLD and HD were also both significantly elevated. Overall, the risk of developing a solid tumor was 2.79 (95% CI, 1.97 to 3.74), which is an excess risk of 23.21 new solid tumors per 10,000 persons/yr. Risks for individual solid tumor types were significantly increased for melanomas, brain tumors, and tumors of the oral cavity (Table 4).
The risk of developing a PTM was also examined according to age at time of SCT (Table 5 ). In this analysis, those patients who were less than 10 years of age at the time of SCT have accumulated a 60-fold higher risk of developing any PTM and a 33-fold higher risk of that tumor being a nonhematopoietic solid tumor. Although somewhat lower risks were found in the successively older age categories, the risks all remained significantly elevated for each age group, with the exception of the risk for solid tumors in individuals who were more than 40 years of age at the time of SCT.
Twenty years of follow-up is now available on this cohort of patients. The overall cumulative incidence of any PTM was 6.9% (95% CI, 5.2% to 8.6%) at 20 years post-SCT (Fig 1 ), and this figure has continued to increase by just under 2% with each successive 5-year follow-up period with no indication of a plateau developing (Table 6).
After the first 5 years of follow-up, the majority of this overall risk is driven by the incidence of solid tumors, which by 20 years post-SCT have a cumulative incidence of 3.8% (95% CI, 2.2% to 5.4%; Fig 2 ). The incidence of PTLD was 1.4% at 20 years (95% CI, 1.0% to 1.8%) and had plateaued by 10 years post-SCT. Similarly, the incidence for MDS/AML was 1.4% at 20 years (95% CI, 0.9% to 1.9%), with a plateau occurring by 10 years after transplant (Fig 2).
Risk Factors for Development of PTMs Solid tumors. A total of 62 solid tumors developed post-SCT in 55 patients. The only variable in Cox regression analysis that was associated with an increased risk of solid tumor development was age  20 years at time of SCT (relative risk [RR], 2.0; 95% CI, 1.1 to 3.5; P = .03). There was no increased risk of solid tumors in patients who received TBI (RR, 1.5; 95% CI, 0.7 to 3.0; P = .27), but in this cohort, 78% of patients were treated with preparative regimens that included TBI or total lymphoid irradiation. Forty-two percent of patients died from their posttransplant solid tumor. The median survival was 4.5 years. Survival at 5 years was 44% (95% CI, 27% to 61%; Fig 3). Among survivors only, the median survival is 1.9 years (range, 7 days to 15 years).
PTLD. PTLD was diagnosed in 43 patients at a median of 0.3 years post-SCT (range, 0.1 to 7.3 years). All but one case was diagnosed in patients receiving an allogeneic SCT. In the Cox regression analysis, factors associated with an increased risk of PLTD included use of a mismatched related donor (RR, 9.0; 95% CI, 0.2 to 40.9), primary diagnosis of an immune deficiency (RR, 2.7; 95% CI, 1.1 to 6.6) or CML (RR, 2.5; 95% CI, 1.2 to 4.9), use of antithymocyte globulin (ATG) either in the preparative regimen or for treatment of GVHD (RR, 3.7; 95% CI, 1.7 to 8.3), T-cell depletion (RR, 4.0; 95% CI, 1.9 to 8.1), and grade 3–4 acute GVHD (RR, 2.4; 95% CI, 1.1 to 5.2). Only nine of the 43 patients diagnosed with PTLD survived, and in 15 patients the diagnosis of PTLD was made postmortem. Median survival was 36 days, and the 1-year survival rate was 25% (95% CI, 12% to 38%). Among survivors, the median survival is 2.2 years (range, 41 days to 12.8 years). MDS/AML. Of the 34 patients with MDS or AML, the majority of cases (n = 30), developed in patients who had received an autologous SCT, although two patients developed MDS/AML after related-donor SCT and two patients developed MDS/AML after unrelated donor SCT. In the patients with allogeneic donors, the MDS developed in recipient cells and represented morphologically and cytogenetically distinct abnormalities compared with the patients with prior AML or CML. The Cox regression analysis was restricted to patients receiving autologous transplants for a primary diagnosis of non-Hodgkin’s lymphoma, HD, or multiple myeloma (n = 452 at risk), of which 30 patients developed MDS/AML. There was a trend toward a higher risk of MDS/AML in patients who were older than 35 years of age at the time of SCT (RR, 2.1; 95% CI, 0.9 to 5.1; P = .09). The risk of MDS/AML was higher in patients who received peripheral-blood stem cells as their stem cell source (RR, 3.1; 95% CI, 1.3 to 7.1; P = .01). In this Cox regression analysis there was no effect on the development of MDS/AML because of sex, conditioning regimen received, time period of SCT (by 5-year periods from 1980 to 2000), or primary diagnosis.
Of the 34 patients who developed MDS/AML, 27 have died. Median actuarial survival is 303 days, and the survival rate at 1 year after diagnosis of MDS/AML is 34% (95% CI, 15% to 53%; Fig 3 Multiple PTMs. Eight patients have developed two PTMs, and one patient has developed three PTMs. All were solid tumors except for two patients with MDS/AML. In these patients, the first PTM was diagnosed at a median of 3.9 years post-SCT, and the second PTM was diagnosed at a median of 6.3 years post-SCT. Three of these patients had a second occurrence of a skin cancer (basal cell or squamous cell), but all others developed two distinct new malignancies. Five patients died of their second PTM, and one patient died from progression of MDS, which had developed as the first post-SCT malignancy. Three patients remain alive: one who survived PTLD and carcinoma-in-situ, and two who have had multiple occurrences of basal cell carcinoma.
This analysis of new malignancies occurring after SCT represents one of the largest reported person-years of follow-up from patients treated and followed at a single institution. With the additional length of follow-up and patient accrual that has taken place since our original report in 1996, the total number of PTMs has nearly tripled, although approximately 50% of the new PTM cases developed in patients who had already received their SCT before the cutoff date of the first analysis (January 1, 1995). Overall, patients who have received an SCT have an eight-fold higher incidence of developing a new malignancy after transplant than the incidence expected in the general population. The major factors contributing to this risk as determined from this analysis are three-fold: MDS/AML occurring after autologous SCT, PTLD in the postallogeneic SCT setting, and the development of solid tumors in any post-SCT patient, which continue to steadily increase during each successive 5-year follow-up period. Forty-five percent of our patient population undergoing SCT was less than 20 years of age, and this group developed 36% of the PTMs that were seen. The highest overall risk of developing a PTM was found in children less than 10 years of age who had a 60-fold increased risk, and in those between 10 and 19 years of age who had a 19-fold higher risk of malignancy compared to the age-matched general population. However, 50% of this risk was attributable to the incidence of PTLD in patients less than 20 years of age. There are several reasons for the predominance of PTLD in this age group. First, all patients with immunodeficiencies were children, and these children have a higher incidence of lymphoma including PTLD.17 Second, in comparison with the adult patients in our cohort, relatively few children underwent autologous SCT. In addition, our donor selection policies allow for HLA mismatches with related or unrelated donors in children, and HLA mismatch has been associated with a higher risk of PTLD in our data and in other reports.18,19 Despite this contribution from PTLD, it is important to note that children less than 10 years of age also had a 33-fold higher risk of solid tumors and that these included types of tumors that are typically rare in children, including melanoma, renal cell carcinoma, breast carcinoma, and mucoepidermoid carcinoma of the parotid. The results from this study are similar to those reported in two other studies in which, for children with leukemia, the risk for any PTM was 45 times higher than that for the general population and the risk of a solid tumor was 34 times higher.19 In the other analysis, all diagnoses were included and the risk of solid tumor development was higher in children as compared with adults (36.6 times higher in those < 10 years of age and 4.6 times higher in children 10 to 19 years of age).1 Survivors from our analysis who underwent SCT as children currently contribute some of the longest follow-up periods in this cohort, and it will be extremely important to maintain ongoing follow-up with them to determine if, and how, their risks for the development of new malignancies change as they continue to age. The most significant risk for any PTM was for t-MDS/AML, which in this cohort was 300-fold higher than that expected in the general population. This calculation was based on the person-years of follow-up for the entire cohort, not just autologous transplant recipients, and thus, this risk would be even higher if autologous transplants were considered separately. Posttransplant MDS/AML is a well-recognized complication of autologous SCT.6,8,25,26 Data indicate that exposures such as the duration of pretransplant chemotherapy; treatment with alkylator therapy or mechlorethamine, vincristine, procarbazine, prednisone therapy for HD; and TBI in the preparative regimen for SCT are all risk factors for the development of t-MDS or AML.27–30 In addition, we have demonstrated that the use of PBSCs was an independent risk factor for the development of posttransplant MDS/AML. This association has been reported previously from the University of Minnesota3,8 and from at least one other investigator.31 There are several potential explanations for this finding. In our patients, PBSCs are collected after chemotherapy priming and growth factor mobilization. It is possible that the cells are harvested in a state of incomplete DNA repair after cytotoxic chemotherapy, cryopreserved, and then subsequently reinfused and stimulated to proliferate. It also is possible that PBSC products will be contaminated with a higher percentage of cells that are already preleukemic from prior therapy. Finally, the use of PBSCs has replaced bone marrow in the modern transplant era at the same time that pretransplant therapies have become much more intensive and when the detection of cytogenetic abnormalities in bone marrow has become more sensitive. These factors, along with increased awareness of the problem and therefore closer patient follow-up, could all contribute to the increased number of patients that are being diagnosed. One of the most significant findings of this study was that the risk of solid tumors continues to increase with each successive 5 years of follow-up, and that with more than 20 years of follow-up in this cohort, the cumulative incidence is close to 4%. This incidence is lower than the previous report from this institution and some other studies in which the incidence estimates were calculated by the Kaplan-Meier method.23 Our calculations were based on cumulative incidence estimates that considered deaths from other causes as competing risks, and therefore, in comparison, numbers in this report are somewhat lower. We did not find a statistically significant association between exposure to TBI and the risk of posttransplant solid tumors. This is in contrast to two other studies in which the risk factors for the development of posttransplant solid tumors included the use of radiation3 or the radiation dose1 in the conditioning regimen, although this correlation has not been found in other studies.2,4 In the present cohort, the majority of patients received a preparative regimen containing TBI or total lymphoid irradiation, making a difference harder to detect. Some of the tumor types that were seen are consistent with those described previously in association with radiation exposure, such as tumors of the salivary gland,32 brain,33 bone,34 and thyroid.35 For allogeneic transplant recipients, the risk of PTLD in our study and others has consistently been strongly associated with HLA disparity, T-cell depletion, and use of ATG.18 We report a cumulative incidence at 10 years of 1.4%, similar to data published recently from the largest reported series of more than 18,000 patients.18 We also report an increased risk of PTLD independently associated with a diagnosis of CML. This association was described previously17 in a univariate analysis of PTLD risk factors but did not achieve significance in the multivariate analysis. In our study, all variables known to be associated with the development of PTLD were included in the final model and were therefore controlled for. PTLD is an early-developing PTM, with a median time to diagnosis of 0.3 years post-SCT. Notably, the diagnosis of PTLD in the SCT setting is not always obvious, as demonstrated by the fact that 35% of our patients were diagnosed on postmortem examination. These patients frequently present with a disseminated or fulminant form of the disease that lacks a well-defined tumor mass or adenopathy and might sometimes be quite difficult to diagnose. Our data are limited because we cannot quantify the potential effect of chemotherapy or radiation therapy received pretransplant in our cohort. In addition, some patients are lost to follow-up, although if anything, this would lead to an underreporting of the true incidence of PTM. Although we report an overall eight-fold increased risk of developing a PTM, patients undergoing autologous SCT are at high risk for MDS/AML but are at low risk for PTLD. Likewise, patients undergoing allogeneic SCTs have a significant risk of PTLD but have a low risk of MDS/AML. The risk of solid tumors is present regardless of transplant type, and this risk continues to increase during each additional year of follow-up. Another factor affecting overall risk assessment is the age at the time of SCT. We have demonstrated that children have a significant risk of PTLD and solid tumors and, therefore, should undergo appropriate ongoing surveillance over their lifetime. Some authors have excluded patients with Fanconi anemia (FA) from analyses of new malignancies post-SCT because of the higher risk for certain forms of cancers in these patients; however, our data set includes three patients with FA who have developed PTMs. One patient had a squamous cell carcinoma of the oral cavity, and two patients had PTLD. These patients were included in our analysis because malignancies that develop in FA patients are captured in SEER data. However, as larger numbers of FA patients undergo SCT and longer follow-up is available, future studies may need to consider these patients separately for some analyses. Finally, additional studies should be directed at defining more clearly what components of the SCT process impart the greatest risk of development of PTM, including data on pre-SCT treatment exposures. Expanded research efforts into issues regarding genetic susceptibility to cancer development or altered metabolism of chemotherapeutic agents will potentially help to determine ways in which risks of developing new malignancies in patients receiving SCT might be reduced.
Supported in part by National Institutes of Health grant no. 1K23CA85503-01A1 and ROI CA789383 (K.S.B.) and by support to the University of Minnesota from the Children’s Cancer Research Fund.
1. Curtis RE, Rowlings PA, Deeg HJ, et al: Solid cancers after bone marrow transplantation. N Engl J Med 336:897–904, 1997
2. Kolb HJ, Socie G, Duell T, et al: Malignant neoplasms in long-term survivors of bone marrow transplantation. Late Effects Working Party of the European Cooperative Group for Blood and Marrow Transplantation and the European Late Effect Project Group. Ann Intern Med 131:738–744, 1999
3. Bhatia S, Ramsay NK, Steinbuch M, et al: Malignant neoplasms following bone marrow transplantation. Blood 87:3633–3639, 1996
4. Bhatia S, Louie AD, Bhatia R, et al: Solid cancers after bone marrow transplantation. J Clin Oncol 19:464–471, 2001 5. Ellis M, Lishner M: Second malignancies following treatment in non-Hodgkin’s lymphoma. Leuk Lymphoma 9:337–342, 1993[Medline] 6. Kollmannsberger C, Hartmann JT, Kanz L, et al: Risk of secondary myeloid leukemia and myelodysplastic syndrome following standard-dose chemotherapy or high-dose chemotherapy with stem cell support in patients with potentially curable malignancies. J Cancer Res Clin Oncol 124:207–214, 1998[CrossRef][Medline]
7. Yakoub-Agha I, de La Salmoniere P, Ribaud P, et al: Allogeneic bone marrow transplantation for therapy-related myelodysplastic syndrome and acute myeloid leukemia: A long-term study of 70 patients—Report of the French Society of Bone Marrow Transplantation. J Clin Oncol 18:963–971, 2000
8. Miller JS, Arthur DC, Litz CE, et al: Myelodysplastic syndrome after autologous bone marrow transplantation: An additional late complication of curative cancer therapy. Blood 83:3780–3786, 1994
9. Pedersen-Bjergaard J, Andersen MK, Christiansen DH: Therapy-related acute myeloid leukemia and myelodysplasia after high-dose chemotherapy and autologous stem cell transplantation. Blood 95:3273–3279, 2000 10. Pedersen-Bjergaard J, Pedersen M, Myhre J, et al: High risk of therapy-related leukemia after BEAM chemotherapy and autologous stem cell transplantation for previously treated lymphomas is mainly related to primary chemotherapy and not to the BEAM-transplantation procedure. Leukemia 11:1654–1660, 1997[CrossRef][Medline]
11. Deeg HJ, Socie G: Malignancies after hematopoietic stem cell transplantation: Many questions, some answers. Blood 91:1833–1844, 1998 12. Laughlin MJ, McGaughey DS, Crews JR, et al: Secondary myelodysplasia and acute leukemia in breast cancer patients after autologous bone marrow transplant. J Clin Oncol 16:1008–1012, 1998[Abstract] 13. Kollmannsberger C, Beyer J, Droz JP, et al: Secondary leukemia following high cumulative doses of etoposide in patients treated for advanced germ cell tumors. J Clin Oncol 16:3386–3391, 1998[Abstract] 14. Swinnen LJ, Costanzo-Nordin MR, Fisher SG, et al: Increased incidence of lymphoproliferative disorder after immunosuppression with the monoclonal antibody OKT3 in cardiac-transplant recipients. N Engl J Med 323:1723–1728, 1990[Abstract] 15. Newell KA, Alonso EM, Whitington PF, et al: Posttransplant lymphoproliferative disease in pediatric liver transplantation: Interplay between primary Epstein-Barr virus infection and immunosuppression. Transplantation 62:370–375, 1996[Medline]
16. Shapiro RS, McClain K, Frizzera G, et al: Epstein-Barr virus associated B cell lymphoproliferative disorders following bone marrow transplantation. Blood 71:1234–1243, 1988 17. Gross TG, Steinbuch M, DeFor T, et al: B cell lymphoproliferative disorders following hematopoietic stem cell transplantation: Risk factors, treatment and outcome. Bone Marrow Transplant 23:251–258, 1999[CrossRef][Medline]
18. Curtis RE, Travis LB, Rowlings PA, et al: Risk of lymphoproliferative disorders after bone marrow transplantation: A multi-institutional study. Blood 94:2208–2216, 1999
19. Socie G, Curtis RE, Deeg HJ, et al: New malignant diseases after allogeneic marrow transplantation for childhood acute leukemia. J Clin Oncol 18:348–357, 2000 20. Ries LAG, Eisner MP, Kosory CL, et al (eds). SEER Cancer Statistics Review, 1973–1998, National Cancer Institute, Bethesda, MD. http://seer.cancer.gov/Publications/CSR1973_1998, 2001
21. Vandenbroucke J: A shortcut method for calculating the 95% percent confidence interval of the standardized mortality ratio. Am J Epidemiol 115:303–304, 1982 22. Lin DY: Non-parametric inference for cumulative incidence functions in competing risks studies. Stat Med 16:901–910, 1997[CrossRef][Medline] 23. Kaplan EL, Meier P: Nonparametric estimation from incomplete observations. J Am Stat Assoc 53:457–481, 1958[CrossRef] 24. Cox DR: Regression models and life-tables. J R Stat Soc 34:187–202, 1972
25. Micallef IN, Lillington DM, Apostolidis J, et al: Therapy-related myelodysplasia and secondary acute myelogenous leukemia after high-dose therapy with autologous hematopoietic progenitor-cell support for lymphoid malignancies. J Clin Oncol 18:947–955, 2000 26. Del Canizo M, Amigo M, Hernandez JM, et al: Incidence and characterization of secondary myelodysplastic syndromes following autologous transplantation. Haematologica 85:403–409, 2000[Medline]
27. Stone RM, Neuberg D, Soiffer R, et al: Myelodysplastic syndrome as a late complication following autologous bone marrow transplantation for non-Hodgkin’s lymphoma. J Clin Oncol 12:2535–2542, 1994 28. Harrison CN, Gregory W, Hudson GV, et al: High-dose BEAM chemotherapy with autologous haemopoietic stem cell transplantation for Hodgkin’s disease is unlikely to be associated with a major increased risk of secondary MDS/AML. Br J Cancer 81:476–483, 1999[CrossRef][Medline] 29. Milligan DW, Ruiz De Elvira MC, Kolb HJ, et al: Secondary leukaemia and myelodysplasia after autografting for lymphoma: Results from the EBMT. EBMT Lymphoma and Late Effects Working Parties European Group for Blood and Marrow Transplantation. Br J Haematol 106:1020–1026, 1999[CrossRef][Medline] 30. Govindarajan R, Jagannath S, Flick JT, et al: Preceding standard therapy is the likely cause of MDS after autotransplants for multiple myeloma. Br J Haematol 95:349–353, 1996[CrossRef][Medline]
31. Andre M, Henry-Amar M, Blaise D, et al: Treatment-related deaths and second cancer risk after autologous stem-cell transplantation for Hodgkin’s disease. Blood 92:1933–1940, 1998 32. Land CE, Saku T, Hayashi Y, et al: Incidence of salivary gland tumors among atomic bomb survivors, 1950–1987: Evaluation of radiation-related risk. Radiat Res 146:28–36, 1996[CrossRef][Medline] 33. Neglia JP, Meadows AT, Robison LL, et al: Second neoplasms after acute lymphoblastic leukemia in childhood. N Engl J Med 325:1330–1336, 1991[Abstract] 34. Tucker MA, D’Angio GJ, Boice JD Jr, et al: Bone sarcomas linked to radiotherapy and chemotherapy in children. N Engl J Med 317:588–593, 1987[Abstract]
35. Tucker MA, Jones PH, Boice JD Jr, et al: Therapeutic radiation at a young age is linked to secondary thyroid cancer. The Late Effects Study Group. Cancer Res 51:2885–2888, 1991 Submitted May 15, 2002; accepted December 13, 2002.
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
